Water-dispersible oral, parenteral, and topical formulations for poorly water soluble drugs using smart polymeric nanoparticles

Abstract

Polymeric nanoparticles with a hydrophobic core and a hydrophilic shell are formed from: 1) N-isopropyl acrylamide (NIPAAM), at a molar ratio of about 50% to about 90%, and preferably 60% for specific delivery routes such as oral or parenteral; either water-soluble vinyl derivatives like vinylpyrolidone (VP) or vinyl acetate (VA), or water insoluble vinyl derivatives like methyl methacrylate (MMA) or styrene (ST), at a molar ratio of about 10% to about 30%; and acrylic acid (AA), at a molar ratio of about 10% to about 30%. The formed nanoparticles may be optionally surface functionalized using reactive groups present in AA, including PEGylation, or conjugation of moieties such as chemotherapeutics, contrasting agents, antibodies, radionucleides, ligands, and sugars, for diagnostic, therapeutic, and imaging purposes. The polymeric nanoparticles are preferably dispersed in aqueous solutions. The polymeric nanoparticles incorporate one or more types of medicines or bioactive agents in the hydrophobic core; on occasion, the medicine or bioactive agent may be conjugated to the nanoparticle surface via reactive functional groups. The polymeric nanoparticles are capable of delivering the said medicines or bioactive agents through oral, parenteral, or topical routes. The polymeric nanoparticles allow poorly water soluble medicines or bioactive agents, or those with poor oral bioavailability, to be formulated in an aqueous solution, and enable their convenient delivery into the systemic circulation.

1. A method for preparing polymeric nanoparticles having a lower critical solution temperature (LCST) above 37° C., comprising the steps of:
 dissolving in aqueous fluid to form micelles from monomers consisting of
 N-isopropylacrylamide (NIPAAM), acrylic acid (AA), and at least one vinyl monomer selected from the group consisting of vinyl acetate, 4-vinyl benzoic acid, methylmethacrylate, vinylmethacrylate, N-vinylpyrrolidone, N-vinyl piperidone, N-vinyl caprolactum, N-vinyl carbazole, and styrene, 
 
 wherein said NIPAAM, said AA, and said vinyl monomer are present at molar ratios of 50-70:10-30:10-30 for NIPAAM:AA:vinyl monomer; 
 polymerizing said micelles; 
 removing unreacted materials from said solution; 
 adding one or more bioactive agents to said solution and allowing said one or more bioactive agents to become entrapped within polymerized micelles in said solution or to become conjugated to the surface of said polymerized micelles in said solution, and functionalizing AA with polyethylene glycol (PEG) amine. 
 
     
     
       2. The method of  claim 1  wherein said polymerizing step includes the step of adding one or more of a crosslinking agent, an activator, and an initiator. 
     
     
       3. The method of  claim 1  wherein said polymerizing step is performed in the presence of an inert gas. 
     
     
       4. The method of  claim 1  wherein said polymerizing step is performed at a temperature ranging from 20° C. to 80° C. 
     
     
       5. The method of  claim 4  wherein said temperature ranges from 30° C. to 40° C. 
     
     
       6. The method of  claim 1  wherein said polymeric nanoparticles have a diameter of 50-100 nm or smaller. 
     
     
       7. The method of  claim 1  wherein at least one of said one or more bioactive agents becomes entrapped within said micelles. 
     
     
       8. The method of  claim 1  wherein at least one of said one or more bioactive agents is a medicament. 
     
     
       9. The method of  claim 1  wherein at least one of said bioactive agents is selected from the group consisting of antineoplastic agents, steroidal compounds, flavonoids, curcuminoids, phytochemicals, antifungal agents, antiviral agents, antibacterial agents, antitubercular agents, and anti-inflammatory agents. 
     
     
       10. The method of  claim 1  wherein at least one of said one or more bioactive agents is selected from the group consisting of Paclitaxel, Docetaxel, Rapamycin, Doxorubicin, Daunorubicin, Idarubicin, Epirubicin, Capecitabine, Mitomycin C, Amsacrine, Busulfan, Tretinoin, Etoposide, Chlorambucil, Chlormethine, Melphalan, Gemcitabine, 5-fluorouracil, (5-FU), Benzylphenylurea (BPU) compounds, Curcumin, Curcuminoids, Cyclopamine, Aciclovir, Indinavir, Lamivudine, Stavudine, Nevirapine, Ritonavir, Ganciclovir, Saquinavir, Lopinavir, Nelfinavir, Itraconazole, Ketoconazole, Miconazole, Oxiconazole, Sertaconazole, Amphotericin B, Griseofulvin Ciprofloxacin, Moxifloxacin, Ofloxacin, Methoxyfloxacin, Pefloxacin, Norfloxacin, Sparfloxacin, Temafloxacin, Levofloxacin, Lomefloxacin, Cinoxacin, Cloxacillin, Benzylpenicillin, Phenylmethoxypenicillin, Erythromycin, Rifampicin, Rifapentin, Ibuprofen, Indomethacin, Ketoprofen, Naproxen, Oxaprozin, Piroxicam, and Sulindac. 
     
     
       11. The method of  claim 1  further comprising the step of surface modification of the particles by functionalizing AA in said polymerized micelles after, said polymerizing step with polyethylene glycol (PEG) amine. 
     
     
       12. The method of  claim 11  wherein a functionalizing step is performed by chemical conjugation between surface carboxylic groups of AA on said polymerized micelles and terminal amine groups of PEG or derivatives of PEG using a cross linker. 
     
     
       13. The method of  claim 1  further comprising the step of surface modification of particles by chemically conjugating the carboxylic groups of the said polymeric micelle with the amine group of a conjugated moiety. 
     
     
       14. The method of  claim 13  wherein said conjugated moiety is selected from the group consisting of a contrasting agent, an antibody, a ligand to a cell surface receptor, a fluorophore, a dye, a radionuclide, a water soluble medicament, and a taste masking agent. 
     
     
       15. A process for preparing polymeric nanoparticles compositions, comprising the steps of
 incorporating one or more medicament or bioactive agent into a polymeric nanoparticle consisting of monomers selected from NIPAAM at a molar ratio ranging from 50 to 70, acrylic acid (AA) at a molar ratio ranging from 10 to 30, and at least one vinyl monomer selected from the group consisting of vinyl acetate, 4-vinyl benzoic acid, methylmethacrylate, vinylmethacrylate, N-vinylpyrrolidone, N-vinyl piperidone, N-vinyl caprolactum, N-vinyl carbazole, and styrene, at a molar ratio ranging from 10 to 30 such that said one or medicament or bioactive agent is incorporated into said polymeric nanoparticle and said polymeric nanoparticle includes NIPAAM, AA, and at least one vinyl monomer present at molar ratios of 50-70:10-30:10-30 for NIPAAM:AA:vinyl monomer; and 
 recovering polymeric nanoparticles after said incorporating step and functionalizing AA with polyethylene glycol (PEG) amine. 
 
     
     
       16. The method of  claim 1  wherein said one or more bioactive agents added in said adding step includes curcumin. 
     
     
       17. The method of  claim 15  wherein said one or more medicament or bioactive agent includes curcumin.